Autoimmune diseases are approaching epidemic levels, estimated to affect 5-8% of the U.S. population. Pathogenesis is attributed, in large part, to self-reactive T cells that recognize auto-antigens in affected tissues and secrete destructive, pro-inflammatory cytokines. Consequently, the differentiation of naive T cells into pro- inflammatory versus tolerogenic T helper cell lineages regulates the immunologic state of the host. T cell receptor (TCR) signals, along with local cytokines, are required for initiating T helpr cell differentiation. Understanding the precise molecular mechanisms contributing to TCR signal integration and T helper cell differentiation is important when considering immunotherapies for T cell-mediated diseases, particularly autoimmunity. We recently demonstrated that Map3k8 transduces TCR signals in naive T cells and helps to specify a Th1 transcriptional program. What is not clear is precisely how Map3k8 impinges upon the multiple TCR signaling pathways to regulate the development and functions of other T helper cell lineages. The goal of this proposal is to determine how the serine-threonine kinase Map3k8 influences TCR signaling, T helper cell differentiation, and autoimmunity. Our central hypothesis is that Map3k8 modulates TCR signal integration and thereby alters lineage commitment and effector functions of T cells in vivo. Aim1 seeks to determine which TCR signaling pathways are defective in Map3k8-/- T cells using gene expression assays, Western blotting, and transcription factor nuclear translocation. Aim2 will examine how Map3k8 influences T helper cell differentiation and will address the roles of specific signaling molecules and pathways in specifying T helper cell fates using in vitro T cell polarization assays and analysis of T cell populations in mice with Map3k8 ablation. Aim3 will determine how Map3k8 contributes to T cell-mediated autoimmunity using genetically altered animal models and Map3k8 pharmacologic inhibitors. Experiments will address the underlying mechanisms of disease (or protection) by analyzing T cell migration, accumulation, and effector functions of Map3k8-/- T cells. Knowledge gained about the role of Map3k8 in TCR signaling networks will not only contribute to our fundamental understanding of normal T cell development and functions, but will also provide insight into the pathogenesis of autoimmune diseases that may ultimately elicit innovative approaches to their treatment and prevention.